EP1587500B1 - Compositions pour administration orale de principes actifs necessitant un masquage du gout - Google Patents

Compositions pour administration orale de principes actifs necessitant un masquage du gout Download PDF

Info

Publication number
EP1587500B1
EP1587500B1 EP03799644.4A EP03799644A EP1587500B1 EP 1587500 B1 EP1587500 B1 EP 1587500B1 EP 03799644 A EP03799644 A EP 03799644A EP 1587500 B1 EP1587500 B1 EP 1587500B1
Authority
EP
European Patent Office
Prior art keywords
composition
active ingredient
minutes
particles
glycerol ester
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP03799644.4A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP1587500A2 (fr
Inventor
Isabelle Chacornac
Patricia Probeck
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aventis Pharma SA
Original Assignee
Aventis Pharma SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Aventis Pharma SA filed Critical Aventis Pharma SA
Priority to SI200332356T priority Critical patent/SI1587500T1/sl
Publication of EP1587500A2 publication Critical patent/EP1587500A2/fr
Application granted granted Critical
Publication of EP1587500B1 publication Critical patent/EP1587500B1/fr
Priority to CY20141100434T priority patent/CY1115401T1/el
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2/00—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic
    • B01J2/02—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic by dividing the liquid material into drops, e.g. by spraying, and solidifying the drops
    • B01J2/04—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic by dividing the liquid material into drops, e.g. by spraying, and solidifying the drops in a gaseous medium
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Definitions

  • the present invention relates to compositions for the oral administration of unacceptable taste active principles, as well as their preparation.
  • the present invention relates to pharmaceutical compositions.
  • Some active ingredients have unacceptable organoleptic properties and are therefore unsuitable for the preparation of pediatric formulations or oral formulations intended for subjects whose swallowing is difficult and can cause problems. For these reasons, some major products are deprived of pediatric formulation and some subjects are deprived of treatment by means of these active ingredients, which can have extremely detrimental or even vital consequences.
  • compositions intended for oral administration can be developed and provide a taste masking sufficient to be acceptable and in particular allow the administration of pharmaceutical compositions in the young child or in subjects not being treated. in a state of swallowing.
  • compositions according to the invention comprise from 15 to 30% of active ingredient mixed with 60 to 80% of a glycerol ester or of a fatty acid, optionally supplemented with a wax, and added with a surfactant. and are prepared by a spray-cooling process that can lead to a particle size of less than 350 microns.
  • the selection of glycerol esters having a suitable pH sensitivity profile allows the release of the active ingredient at acidic pH conditions such as is encountered in the stomach.
  • the glycerol or fatty acid esters employed in the compositions according to the invention have the following characteristics: melting temperature of between 25 ° C. and 100 ° C., preferably between 25 ° and 70 ° C., stability at the melted state.
  • the glycerol ester may be chosen from glycerol stearate or glycerol palmitostearate, especially Précirol®.
  • the glycerol ester is advantageously between 50 and 85% by weight of the total mixture of the composition; it is preferably between 60 and 80% by weight and more particularly between 70 and 80% by weight.
  • the wax which may be optionally added may advantageously be carnauba wax, it may also be chosen from paraffin wax or beeswax or candelilla wax.
  • a wax When a wax is added to the composition, it may be added in a proportion of 4 to 10% by weight of the total mixture of the composition and in a ratio of 5 to 20% with respect to the glycerol ester introduced.
  • a fatty acid is introduced into the composition
  • the latter is advantageously chosen from palmitic, myristic or stearic acid.
  • the fatty acid is introduced in a proportion of 60 to 80% by weight of the total mixture of the composition.
  • the surfactant introduced into the composition is advantageously chosen from lecithins, in particular soy lecithin, or surfactants of the family of sorbitan esters having an HLB of less than 7.
  • the surfactant is added 1 to 3% by weight of the total mixture of the composition.
  • the diameters are advantageously less than 350 ⁇ m for more than 90% of the particles. More particularly, they may be between 100 ⁇ m and 350 ⁇ m for 25 to 65% of the particles and less than 100 ⁇ m for 35 to 75% of the particles.
  • the spray-cooling is carried out by spraying by means of a bifluid nozzle making it possible to obtain the desired particle size, that is to say a small diameter particle size as described above.
  • the preparation of the composition is carried out by mixing the active ingredient in the molten glycerol ester, added with the other excipients.
  • the mixture is sprayed by the bifluid nozzle at the top of a tower in which a cold gas counterflow is optionally introduced to aid the solidification of the sprayed droplets.
  • the device is preferably provided with a fluidized bed to recover the particles and improve the rapidity of solidification.
  • the molten mixture introduced into the two-fluid nozzle is generally heated to between 60 and 100 ° C.
  • the bifluid nozzle advantageously comprises a diameter of 2.5 mm for the liquid section and a torric section of 0.3 mm for the air (or nitrogen) section.
  • the flow of liquid and the flow of air (or nitrogen) sprayed into the nozzle are set beforehand according to the diameters of the sections of the two-fluid nozzle used.
  • the liquid flow rate is set between 1 and 15 kg / h and the air flow rate is set between 2 and 5 m 3 / h.
  • the particle size of the active ingredient initially mixed with the glycerol ester ranges from 2 to 350 microns. In some cases it may be necessary to grind before or after mixing with the glycerol ester and prior to spraying. Preferably the dry grinding is carried out before mixing.
  • the tower used is a tower type prilling tower, but which has been adapted a bifluid nozzle (unlike the usual implementation of prilling).
  • the height of the tower is preferably between 2 and 8 m.
  • the gaseous countercurrent for cooling is advantageously a nitrogen stream or a dry gas stream.
  • the flow rate is a function of numerous factors such as the temperatures, the height of the chamber, the quantities of product, etc. As an indication, it can be set in particular between values: slightly greater than 0 and 350 Nm3 / h.
  • the composition may further contain other additives such as sweetening or taste modifying agents (saccharinate, aspartame, glycerin, vanillin, menthol ... or any other substance normally used in the pharmaceutical industry), flavorings, flow agents, lubricants, ballasts or mineral agents [silicas, aluminum oxide, magnesium oxide, talc .. carbonates (calcium carbonate), phosphates (tricalcium phosphate), lactose, sorbitol, glycine, mannitol, glucose, maltodextrins ...], preservatives (for example sodium metabisulphite, propylene glycol, ethanol or glycerine) agents intended to modify the color.
  • sweetening or taste modifying agents sacharinate, aspartame, glycerin, vanillin, menthol ... or any other substance normally used in the pharmaceutical industry
  • flavorings flow agents
  • lubricants ballasts or mineral agents
  • sicas aluminum oxide, magnesium oxide, tal
  • the present invention relates to all the active ingredients alone or in mixtures, orally administrable and having organoleptic problems, resulting in unacceptability by people to ingest them.
  • the active ingredients are bitter substances, irritating ... or unacceptable flavor.
  • Said active ingredients are compatible with the glycerol ester and its melting point.
  • the active principles when it comes to pharmaceutical active principles, they may belong to any therapeutic class, such as, for example, antibacterials [macrolides (spiramycin, ketolides such as telithromycin, etc.), streptogramins (pristinamycins, such as pyostacine for example, virginiamycin for example), quinolones ...], antifungals (metronidazole ...), antiparasitics (nivaquine %), anti-virals, anti-cancer drugs, analgesics, nonsteroidal anti-inflammatory drugs , antitussives, psychotropic drugs, steroids, medicines for the treatment of allergies, anti-asthmatics, antispasmodics, cardiovascular drugs (roxitromycin for example, etc.), therapeutic agents of the gastrointestinal tract ... It may also be active ingredients, alone or in mixtures, for cosmetic purposes such as vitamins or extracts of plants or animals
  • the present invention has the advantage of effective taste masking combined with an absence or a very low sandy sensation of the composition in the mouth.
  • the bitterness limit depending on the nature of the active ingredient, is measured.
  • 1248 g of the milled suspension are then sprayed via a two-fluid nozzle into a prilling tower previously cooled by a stream of cold nitrogen.
  • the temperature is 0 ° C at the top of the tower and -20 ° C at the bottom of the tower.
  • the air pressure on the bi-fluid nozzle is 1.5 bar, which leads to a spraying air flow rate of 2.3 m 3 / h.
  • the liquid flow rate is 4.7 kg / h.
  • the product is then fluidized for 20 minutes at -20 ° C. and then for 2 hours at 32 ° C.
  • the dissolution kinetics at pH 1 is 92% in 60 minutes for the crude product and 99% in 60 minutes for the particle size cut 100-315 microns.
  • the concentration of active ingredient in the glass of water is 182 mg / l after 5 minutes and 473 mg / l after 15 minutes for the raw granules. It is 89 mg / l after 5 minutes and 280 mg / l after 15 minutes for the granules of the 100-315 ⁇ m section.
  • 704 g of precirol are introduced into a double jacketed reactor whose set-point jacket temperature is set at 75 ° C.
  • 18 g of soy lecithin are added.
  • 182 g of pre-micronized pristinamycin are added to an air jet micronizer and having a median diameter of 2 ⁇ m after grinding. It is stirred for 45 minutes at 800 rpm to obtain a homogeneous suspension.
  • the suspension is then sprayed via a two-fluid nozzle into a prilling tower previously cooled by a stream of cold nitrogen.
  • the temperature is -14 ° C at the top of the tower and -42 ° C at the bottom of the tower.
  • the air pressure on the bi-fluid nozzle is 1.5 bar, which leads to a spraying air flow rate of 2.3 m 3 / h.
  • the liquid flow rate is 10.8 kg / h.
  • the dissolution kinetics at pH 1 for the crude product is 86% in 60 minutes and 97% in 120 minutes.
  • the concentration of active ingredient in the glass of water is 22 mg / l after 5 minutes and 140 mg / l after 15 minutes for the raw granules.
  • telithromycin is visibly soluble in precirol.
  • the suspension is then sprayed via a two-fluid nozzle into a prilling tower previously cooled by a stream of cold nitrogen.
  • the temperature is 0 ° C at the top of the tower and -20 ° C at the bottom of the tower.
  • the air pressure on the bi-fluid nozzle is 1.3 bar, which leads to a spraying air flow of 4 m 3 / h.
  • the liquid flow rate is 8.5 kg / h.
  • the dissolution kinetics at pH 1 for the crude product is 98% in 60 minutes.
  • the concentration of active ingredient in the glass of water is 387 mg / l after 5 minutes and 873 mg / l after 15 minutes for the raw granules. It is 181 mg / l after 5 minutes and 475 mg / l after 15 minutes for the granules of the 100-315 ⁇ m section.
  • the suspension is then sprayed via a two-fluid nozzle into a prilling tower previously cooled by a stream of cold nitrogen.
  • the temperature is -7 ° C at the top of the tower and -29 ° C at the bottom of the tower.
  • the air pressure on the bi-fluid nozzle is 1.3 bar, which leads to a spraying air flow of 4 m 3 / h.
  • the liquid flow rate is 5 kg / h.
  • the dissolution kinetics at pH 1 for the crude product is 77.5% in 60 minutes.
  • the concentration of active ingredient in the glass of water is 90 mg / l after 5 minutes and 340 mg / l after 15 minutes for the raw granules. It is 81 mg / l after 5 minutes and 658 mg / l after 15 minutes for the granules of the 100-315 ⁇ m section.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Medical Preparation Storing Or Oral Administration Devices (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP03799644.4A 2002-12-23 2003-12-19 Compositions pour administration orale de principes actifs necessitant un masquage du gout Expired - Lifetime EP1587500B1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
SI200332356T SI1587500T1 (sl) 2002-12-23 2003-12-19 Sestavki za oralno dajanje učinkovin, ki potrebujejo prikritje okusa
CY20141100434T CY1115401T1 (el) 2002-12-23 2014-06-12 Συνθεσεις για χορηγηση απο του στοματος δραστικων ενωσεων που απαιτουν συγκαλυψη της γευσης

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR0216521A FR2848855B1 (fr) 2002-12-23 2002-12-23 Compositions pour administration orale de principes actifs necessitant un masquage du gout
FR0216521 2002-12-23
PCT/FR2003/003813 WO2004058137A2 (fr) 2002-12-23 2003-12-19 Compositions pour administration orale de principes actifs necessitant un masquage du gout

Publications (2)

Publication Number Publication Date
EP1587500A2 EP1587500A2 (fr) 2005-10-26
EP1587500B1 true EP1587500B1 (fr) 2014-03-12

Family

ID=32406402

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03799644.4A Expired - Lifetime EP1587500B1 (fr) 2002-12-23 2003-12-19 Compositions pour administration orale de principes actifs necessitant un masquage du gout

Country Status (14)

Country Link
EP (1) EP1587500B1 (el)
JP (1) JP4676763B2 (el)
AU (1) AU2003299360B2 (el)
BR (1) BR0317654A (el)
CA (1) CA2510373C (el)
CY (1) CY1115401T1 (el)
DK (1) DK1587500T3 (el)
ES (1) ES2470371T3 (el)
FR (1) FR2848855B1 (el)
IL (1) IL169343A (el)
MX (1) MXPA05005640A (el)
PT (1) PT1587500E (el)
SI (1) SI1587500T1 (el)
WO (1) WO2004058137A2 (el)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL1034065C2 (nl) 2007-06-29 2008-12-30 Friesland Brands Bv Bereiding van deeltjes.
FR2959130A1 (fr) 2010-04-21 2011-10-28 Sanofi Aventis Procede de preparation de compositions pharmaceutiques destinees a l'administration par voie orale comprenant un ou plusieurs principes actifs et les compositions les comprenant.
FR2968992B1 (fr) 2010-12-16 2013-02-08 Sanofi Aventis Comprime pharmaceutique orodispersible a base de zolpidem
FR2968995B1 (fr) 2010-12-16 2013-03-22 Sanofi Aventis Composition pharmaceutioue pour une administration par voie orale destinee a eviter le mesusage
FR3000400B1 (fr) 2012-12-27 2019-06-21 Virbac Suspension huileuse de metronidazole
EP3076947B1 (en) * 2013-12-04 2018-06-13 Hovione Scientia Limited Contrast media containing taste masking formulations
FR3027802B1 (fr) * 2014-10-31 2018-03-02 Ethypharm Granules de principe actif a double masquage de gout, leur procede de preparation et comprimes orodispersibles les contenant

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59122425A (ja) * 1982-12-27 1984-07-14 Kaken Pharmaceut Co Ltd 持続性製剤およびその製造法
NL193682C (nl) * 1987-05-14 2000-07-04 Glaxo Group Ltd Beklede cefuroximaxetilsamenstelling.
FR2657257B1 (fr) * 1990-01-19 1994-09-02 Rhone Poulenc Sante Procede de preparation de medicaments sous forme de perles.
JP3155028B2 (ja) * 1991-06-10 2001-04-09 大川原化工機株式会社 噴霧乾燥造粒装置
JPH05309314A (ja) * 1992-05-07 1993-11-22 Sumitomo Pharmaceut Co Ltd コーティング方法
ES2107685T3 (es) * 1992-10-16 1997-12-01 Glaxo Group Ltd Composiciones de ranitidina que enmascaran su sabor.
NZ505123A (en) * 1997-12-19 2003-07-25 Smithkline Beecham Corp Process for manufacturing bite-dispersion tablets by compressing medicaments and other ingredients into granulates then compressing the granulates and other ingredients into tablets, and the tablets thereof
JP2000103730A (ja) * 1998-07-31 2000-04-11 Otsuka Pharmaceut Co Ltd 服用感が改善された医薬組成物
US6209479B1 (en) * 1998-12-30 2001-04-03 Aeromatic-Fielder Ag Apparatus for coating tablets
CN1343128B (zh) * 1999-03-17 2010-04-21 第一制药株式会社 药物组合物

Also Published As

Publication number Publication date
CA2510373A1 (fr) 2004-07-15
BR0317654A (pt) 2005-12-20
CY1115401T1 (el) 2017-01-04
MXPA05005640A (es) 2005-07-27
FR2848855A1 (fr) 2004-06-25
ES2470371T3 (es) 2014-06-23
WO2004058137A3 (fr) 2005-04-14
IL169343A0 (en) 2007-07-04
DK1587500T3 (da) 2014-06-23
IL169343A (en) 2011-06-30
PT1587500E (pt) 2014-06-24
SI1587500T1 (sl) 2014-07-31
EP1587500A2 (fr) 2005-10-26
WO2004058137A2 (fr) 2004-07-15
AU2003299360B2 (en) 2009-10-29
JP2006515592A (ja) 2006-06-01
AU2003299360A1 (en) 2004-07-22
CA2510373C (fr) 2014-09-30
JP4676763B2 (ja) 2011-04-27
FR2848855B1 (fr) 2005-02-11

Similar Documents

Publication Publication Date Title
EP0438359B1 (fr) Procédé de préparation de médicaments sous forme de perles
EP2560612B1 (en) Method for preparing pharmaceutical compositions intended for oral administration comprising one or more active ingredients and the compositions comprising same
JP2001514210A (ja) ２つのコーティング層を有する医薬組成物
CA2162299C (fr) Composition pharmaceutique pour l'administration orale de flavonoides
EP0956010B1 (fr) Microspheres pharmaceutiques d'acide valproique pour administration orale
EP2983650B1 (en) Oral pharmaceutical composition comprising taste-masked n-acetylcysteine
EP1587500B1 (fr) Compositions pour administration orale de principes actifs necessitant un masquage du gout
EP1646379B1 (fr) Nouvelle composition pharmaceutique solide comprenant de l amisulpride
US8383146B2 (en) Compositions for oral adminstration of active principles requiring masking of taste
EP3761964A1 (fr) Formulation gastro-protégée et hydrophobe d'au moins un principe actif et procédé d'obtention
WO1994025006A1 (en) Taste-masking pharmaceutical compositions and methods for making the same
FR2784895A1 (fr) Comprime a croquer a gout masque et liberation immediate du principe actif et procede de fabrication
EP0911038B1 (fr) Composition anhydre à base de lactulose
EP0438358B1 (fr) Nouvelle forme unitaire, solide et poreuse comprenant des particules sous forme de perles ainsi que sa préparation

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK

17P Request for examination filed

Effective date: 20051014

RBV Designated contracting states (corrected)

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20090916

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

INTG Intention to grant announced

Effective date: 20130918

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

Free format text: NOT ENGLISH

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 655753

Country of ref document: AT

Kind code of ref document: T

Effective date: 20140315

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

Free format text: LANGUAGE OF EP DOCUMENT: FRENCH

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 60345862

Country of ref document: DE

Effective date: 20140424

REG Reference to a national code

Ref country code: RO

Ref legal event code: EPE

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2470371

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20140623

Ref country code: DK

Ref legal event code: T3

Effective date: 20140616

REG Reference to a national code

Ref country code: PT

Ref legal event code: SC4A

Free format text: AVAILABILITY OF NATIONAL TRANSLATION

Effective date: 20140611

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

REG Reference to a national code

Ref country code: NL

Ref legal event code: T3

REG Reference to a national code

Ref country code: EE

Ref legal event code: FG4A

Ref document number: E009237

Country of ref document: EE

Effective date: 20140606

REG Reference to a national code

Ref country code: SK

Ref legal event code: T3

Ref document number: E 16437

Country of ref document: SK

Ref country code: GR

Ref legal event code: EP

Ref document number: 20140401140

Country of ref document: GR

Effective date: 20140718

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 60345862

Country of ref document: DE

REG Reference to a national code

Ref country code: HU

Ref legal event code: AG4A

Ref document number: E021202

Country of ref document: HU

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DK

Payment date: 20141211

Year of fee payment: 12

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GR

Payment date: 20141112

Year of fee payment: 12

Ref country code: CZ

Payment date: 20141205

Year of fee payment: 12

Ref country code: FI

Payment date: 20141209

Year of fee payment: 12

Ref country code: IE

Payment date: 20141209

Year of fee payment: 12

Ref country code: MC

Payment date: 20141028

Year of fee payment: 12

Ref country code: SK

Payment date: 20141119

Year of fee payment: 12

Ref country code: BG

Payment date: 20141010

Year of fee payment: 12

Ref country code: SE

Payment date: 20141211

Year of fee payment: 12

Ref country code: EE

Payment date: 20141106

Year of fee payment: 12

Ref country code: LU

Payment date: 20141211

Year of fee payment: 12

Ref country code: RO

Payment date: 20141112

Year of fee payment: 12

Ref country code: ES

Payment date: 20141111

Year of fee payment: 12

Ref country code: CH

Payment date: 20141212

Year of fee payment: 12

26N No opposition filed

Effective date: 20141215

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AT

Payment date: 20141125

Year of fee payment: 12

Ref country code: NL

Payment date: 20141210

Year of fee payment: 12

Ref country code: HU

Payment date: 20141205

Year of fee payment: 12

Ref country code: SI

Payment date: 20141117

Year of fee payment: 12

Ref country code: PT

Payment date: 20141219

Year of fee payment: 12

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 60345862

Country of ref document: DE

Effective date: 20141215

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IT

Payment date: 20141204

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CY

Payment date: 20141128

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 20141211

Year of fee payment: 12

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 13

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20151231

REG Reference to a national code

Ref country code: PT

Ref legal event code: MM4A

Free format text: LAPSE DUE TO NON-PAYMENT OF FEES

Effective date: 20160620

REG Reference to a national code

Ref country code: DK

Ref legal event code: EBP

Effective date: 20151231

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CZ

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20151219

Ref country code: CY

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20151219

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20151219

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20151231

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: SE

Ref legal event code: EUG

REG Reference to a national code

Ref country code: EE

Ref legal event code: MM4A

Ref document number: E009237

Country of ref document: EE

Effective date: 20151231

Ref country code: AT

Ref legal event code: MM01

Ref document number: 655753

Country of ref document: AT

Kind code of ref document: T

Effective date: 20151219

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160620

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20151220

Ref country code: RO

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20151219

REG Reference to a national code

Ref country code: SK

Ref legal event code: MM4A

Ref document number: E 16437

Country of ref document: SK

Effective date: 20151219

REG Reference to a national code

Ref country code: NL

Ref legal event code: MM

Effective date: 20160101

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

REG Reference to a national code

Ref country code: SI

Ref legal event code: KO00

Effective date: 20160829

REG Reference to a national code

Ref country code: GR

Ref legal event code: ML

Ref document number: 20140401140

Country of ref document: GR

Effective date: 20160707

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BG

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160930

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160101

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20151231

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20151219

Ref country code: HU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20151220

Ref country code: EE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20151231

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20151231

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 14

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20151219

Ref country code: SI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20151220

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20151219

Ref country code: GR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160707

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20151219

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20170126

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20151231

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: TR

Payment date: 20141219

Year of fee payment: 12

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20151220

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20151219

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20151219

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 15

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20201112

Year of fee payment: 18

Ref country code: DE

Payment date: 20201208

Year of fee payment: 18

Ref country code: GB

Payment date: 20201210

Year of fee payment: 18

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 60345862

Country of ref document: DE

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20211219

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20211219

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20220701

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20211231